DESCRIPTION: Periodontal disease, characterized by destruction of periodontal tissues, is more prevalent and severe in patients with diabetes as compared to those without diabetes. Although it is known that matrix metalloproteinases (MMPs) and inflammatory cytokines play a critical role in destructive periodontal disease, the periodontal expression of MMPs and cytokines in diabetic patients has not been elucidated and compared to that in nondiabetic patients. Furthermore, it is not clear how diabetes-associated pathogenic factors such as hyperglycemia interplay with bacterial virulence factors to promote periodontal tissue destruction. Recently, we found that long-term pre-exposure of U937 histiocytes and human monocyte-derived macrophages to high glucose 25 mM) markedly augments lipopolysaccharide (LPS)- stimulated MMP and cytokine expression when compared to pre-exposure to normal glucose 5 mM), suggesting that a synergism between hyperglycemia and the bacterial virulence factor may enhance the periodontal expression of MMPs and cytokines in diabetic patients. In this research project, we have two Specific Aims: First, we will further determine the signaling and molecular mechanisms involved in the synergisms between high glucose and IPS on MMP and cytokine expression. We posit that high glucose augments MMP and cytokine expression by enhancing LPS-activated signaling pathways. Second, we will illustrate the periodontal expression of MMPs and cytokines in diabetic and nondiabetic patients, and establish a relationship between diabetes and periodontal expression of MMPs and cytokines. We postulate that periodontal expression of MMPs and cytokines is associated with hyperglycemia. In this research project, we will use protein and DMA arrays and other new techniques, and combine basic research with patient study. The novel information obtained from this study will elucidate the potential targets for the therapeutic intervention of diabetes-associated periodontal disease.